Nicotine lozenge compositions

ABSTRACT

The present invention relates to nicotine lozenge compositions comprising reduced levels of buffering agents from traditional nicotine lozenges and which provide optimal oral pH and prompt nicotine absorption in a smaller, more convenient dosage form.

FIELD OF THE INVENTION

The present invention relates to nicotine lozenge compositions whichhave improved sensory profiles and user compliance. The presentinvention further relates to nicotine lozenge compositions whichcomprise reduced levels of buffering agents that provide an optimal oralpH and, thus, enhance nicotine absorption through oral or mucosaltissues.

BACKGROUND OF THE INVENTION

It is generally known that active as well as passive smoking of tobaccoproducts, such as cigarettes, cigars and pipe tobacco presents serioushealth risks to the user and those subjected to secondary smoke. It isalso known that the use of smokeless forms of tobacco, such as chewingtobacco, spit tobacco and snuff tobacco, presents serious health risksto the user. Furthermore, the use of tobacco products in public areas isincreasingly either restricted or socially unacceptable. Consequently,smokers and other tobacco users often try to quit the potentially deadlyhabit. Others may be forced to cut back on the amount of tobacco used asemployment and social settings increasingly restrict smoking and othertobacco use.

Although the damaging effects of tobacco usage are well known, mostindividuals who are nicotine dependent have great difficulty inovercoming their dependence on nicotine, typically in cigarette form.The difficulty arises in part due to the highly addictive nature ofnicotine and the strong nicotine withdrawal symptoms that can occur whenone begins to deprive the body of the nicotine to which it has growndependent. Indeed, overcoming nicotine withdrawal symptoms is a criticalchallenge for those attempting to conquer nicotine dependence.

Nicotine withdrawal symptoms, particularly nicotine cravings, may arisein several ways. For instance, studies have shown that following a quitattempt, smokers report moderate levels of steady nicotine cravingthroughout the day. This craving can prove too much for some, leading torelapse and a return to tobacco usage for some of those individualsattempting to quit. In addition to steady cravings, smokers may alsoexperience episodic, or acute, cravings. These acute cravings may beprovoked by a number of stimuli, such as exposure to smoking relatedcues, seeing smoking paraphernalia, being in proximity to others engagedin smoking, or inhaling second hand smoke. Such episodic cravings mayalso lead to relapse if effective coping measures are not employed bythe individual.

In an attempt to assist those who wish to eliminate or reduce tobaccousage, efforts have been made to provide those in need with some levelof nicotine craving relief. Historically, these efforts have focused onthe activity and administration of nicotine itself. This nicotinereplacement therapy (NRT) helps to combat the intense nicotinewithdrawal symptoms encountered by many individuals upon quittingsmoking or other tobacco usage. In recent years, NRT has beensuccessfully commercialized in both the United States and elsewhere.Such commercial NRT offerings include nicotine gums, and nicotinetransdermal patches (e.g., NICODERM® brand patches and NICORETTE® brandgums sold by GlaxoSmithKline Consumer Healthcare).

In addition to traditional gums and patch NRT offerings, more recently,nicotine containing lozenges have been introduced commercially bothwithin and outside the United States. For example, COMMIT®, brandlozenges offer individuals an alternative form of NRT. U.S. Pat. No.5,110,605 to Acharya et al. relates to lozenge compositions whichcomprise polycarbophil and alginic acid components. Other examples ofnicotine containing lozenge formulations are found in a number ofpublications, including but not limited to, U.S. Pat. No. 4,967,773 toShaw; U.S. Pat. No. 5,549,906 to Santus; U.S. Pat. No. 6,183,775 toVentouras; and WO 2007/104575 to Axelsson et al. Similarly, U.S. Pat.Nos. 5,593,684; 5,721,257 and 5,362,496 (all to Baker et al.) disclosemethods and therapeutic systems for smoking cessation, utilizing bothtransdermal nicotine delivery for obtaining base-line nicotine plasmalevels, and transmucosal administration of nicotine to satisfy transientcravings. While such means are useful as aids to reduce or quit smoking,there is an ongoing need to provide improved lozenge formulations toassist individuals in quitting nicotine usage. In particular, thereremains a need to develop lozenge forms which provide the traditionallevels of craving relief to an individual but are designed to improveuser compliance with an NRT program. In particular, a smaller lozenge,with comparable or faster dissolution time and onset of craving reliefwould boost user compliance with an NRT regimen and would beadvantageous.

The present invention provides nicotine lozenge formulations withimproved organoleptics, improved onset of delivery and reduceddissolution time in the oral cavity and, thereby, improved usercompliance.

SUMMARY OF THE INVENTION

The present invention relates to nicotine containing lozengecompositions which comprise lower levels of alkaline buffering agentsthan traditional nicotine containing oral dosage forms while achievingoptimal and palatable oral pH and enhancing nicotine absorption throughthe oral cavity. The present invention comprises alkaline bufferingagents both within and external to a master granulation, while overallincorporating lower levels of the alkaline buffering agent within thecomposition versus traditional lozenges in which the buffering agentsare uniformly dispersed in the intragranular portion. Advantageously,the compositions of the present invention can be formulated in muchsmaller lozenge than traditional nicotine containing lozenges and, thus,have reduced dissolution times in the oral cavity while still achievingsignificant nicotine plasma level and obtaining comparable nicotinepharmacokinetic profiles to the traditional lozenge. By reducingdissolution time, optimizing the oral pH and improving the speed ofnicotine absorption, patient compliance is also improved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the dissolution profile (as % release versus time) of anicotine containing lozenge of the formulation of Example 1 wherein thebuffering agent is present both within and extragranular to the mastergranules versus a lozenge of the formulation of Example 2 wherein allbuffering agent is present intragranular to the master granules. USPapparatus I was used to conduct the dissolution study.

FIG. 2 depicts the pH in water over time upon dissolution of a lozengeof the formulation of Example 1 versus that of a lozenge of theformulation of Example 2 and that of Example 5 wherein all bufferingagent is present intragranular to the master granules. USPdisintegration apparatus was used to measure the water pH increased upondisintegration and dissolution of lozenges.

FIG. 3 depicts the nicotine plasma concentration of a lozenge of thepresent invention (Example 1) versus that of a traditional lozenge(Example 2) in healthy smokers.

DETAILED DESCRIPTION OF THE INVENTION

All publications including, but not limited to, patents and patentapplications cited in this specification are incorporated herein byreference as though fully set forth.

Unless otherwise specified all parts and percentages set forth hereinare weight percentages based on the total weight of the relevant orallydissolving lozenge being described.

Unless otherwise stated as used herein, the term “a” or “an” includesone or more of the components modified.

The present invention may comprise, consist of, or consist essentiallyof the components set forth below, unless otherwise stated.

As described above, the formulations of the present invention comprise amaster granule component as well as an extragranular component.

The use of “master granule” formulations is common in solid dosage formssuch as tablets and compressed lozenges. Typically, the mastergranulation is made to improve the processability of a solid dosage formand to reducing friability during transportation and handling. In theabsence of a master granule component, tablets or lozenges where highlevels of non-direct compressible diluents are used can be difficult toprocess or result in a product with high friability. In a typicalnicotine lozenge formulation, such as that of the COMMIT lozenge,fillers or diluents (hereinafter collectively referred to as “diluents”)and dissolution modifiers or binding agents (hereinafter collectivelyreferred to as “dissolution modifiers”) are generally granulatedtogether along with buffering agents to form these master granules.Active agents, and other optional excipients and flavoring agents, arethereafter blended with the master granules, prior to compressing, andmake up the “extragranular” component of these traditional lozengeformulations.

In contrast, however, in the formulations of the present invention, themaster granules comprise at least one diluent, at least one dissolutionmodifier and at least one buffering agent. The master granules are thencombined with a nicotine active, additional alkaline buffering agentand, optionally, taste masking agents, flavors, sweeteners, chelatingagents, anti-oxidants or preservatives, processing aids such as glidantsor lubricants, or colorants.

As used herein, the term “nicotine active” refers to one or morecompounds selected from: nicotine; derivatives of nicotine, such asnicotine salts and nicotine complexes; tobacco extract or leaf; anycompounds or compositions that produce a similar physiological effect asnicotine, such as lobeline; and mixtures thereof. A variety of nicotineactives are well known in the art and are commercially available.Suitable nicotine actives for use herein include, but are not limitedto, nicotine monotartrate, nicotine bitartrate, nicotine hydrochloride,nicotine dihydrochloride, nicotine sulfate, nicotine zinc chloridemonohydrate, nicotine salicylate, nicotine oil, nicotine complexed withcyclodextrin, polymer resins such as nicotine polacrilex, and mixturesthereof. The nicotine active may be used in one or more distinctphysical forms well known in the art, including free base forms,encapsulated forms, ionized forms and spray-dried forms. In oneembodiment, the nicotine active is nicotine polacrilex.

In one embodiment the nicotine polacrilex is present in an amount fromabout 1 mg to about 10 mg of nicotine base per dosage form. Thepercentage of nicotine polacrilex per dosage form is from about 2% toabout 20% of the total weight of the dosage form.

Importantly, in the present invention, both the nicotine active and thecounter ions from the alkaline buffering agent exist in theextra-granular space within the present formulations. Where the nicotineactive is a polymer resin, such as nicotine polacrilex, nicotine formsan ionic complex with polacrilex which is stable and water insoluble.Once administered, the release of nicotine from the polymer resincomplex occurs through an ionic exchange process with counter ions thatalso become available through dissolution in the oral cavity. Thisresults in the release of free nicotine from the water insoluble resinswhich is then ready for absorption through the oral mucosa. In atraditional lozenge formulation, more than double the amount ofbuffering agents of the present invention are incorporated within themaster granule only. Upon disintegration, nicotine is still bound to thepolacrilex as there are not sufficient cations in the saliva to exchangeand release the nicotine from the complex. Thus, the nicotine of thesetraditional lozenges is not available until the master granules dissolveand release the buffer (counter ions) in the oral cavity. Because thebuffering agents are granulated with the binding dissolution modifiersthe release of the buffering agents is somewhat slowed. Once released,the buffer first exchanges with the nicotine, and then must raise the pHof the oral cavity to prompt nicotine absorption through the mucosaltissues. As a result, there is delay before the absorption of nicotinefrom these traditional lozenges occurs.

By incorporation of the buffering agents, both within and external tothe master granules, it has been found that lower levels of thebuffering agents are needed to achieve optimal and palatable pH in theoral cavity and faster nicotine absorption. In the current invention,the nicotine is immediately freed from the nicotine polacrilex complexby the presence of the counter ions available in the extragranularbuffering agent upon disintegration. Thus, all buffering agent laterreleased from the master granules is available to raise the oral cavitypH and drive nicotine absorption through the mucosal tissues. It is,thus, important that no dissolution modifiers are present in theextragranular portion of the formulation as this may retard the increasein oral pH by slowing the dissolution of the extragranular portion ofthe formulation.

FIG. 2 depicts the increase in pH achieved by the formulations of thepresent invention (Example 1) versus lozenges wherein the bufferingagents are completely subsumed within the master granulation (Examples 2and 5). In particular, where similar low levels of buffers are used(Example 1 vs. Example 6), the maximum pH achieved is indeed higher,where the buffering agent is present both within and external to themaster granule, rather than within the master granule only. In addition,FIG. 2 depicts that a substantial reduction in buffering agents is stillsufficient to achieve optimal pH to drive nicotine absorption when thebuffer is present both within and external to the master granules.(Example 2 vs. Example 1).

Alkaline buffering agents suitable for use in the present inventioninclude, but are not limited to, sodium carbonate, sodium bicarbonate,potassium phosphate, potassium carbonate and potassium bicarbonate. Inone embodiment, the buffering agents are selected from potassiumbicarbonate, sodium carbonate and mixtures thereof. The buffering agentsare incorporated within the master granules as well as incorporatedwithin the extra-granular space between said master granules. The totalamount of buffer present in the compositions of the present invention isfrom about 5 mg to about 20 mg. In one embodiment the total amount ofbuffer present in the compositions of the present invention is fromabout 8 mg to about 12 mg. In one embodiment the ratio of nicotinepolacrilex to total buffer is from about 3:1 to about 1:3 by totalweight.

As indicated above the alkaline buffering agents are incorporated bothwithin the master granules (intragranular) and within the extragranularspace between said master granules (extragranular). In general, theamount of buffering agent present in the compositions of the presentinvention, expressed as a ratio of intragranular buffering agent toextragranular buffering agent is from about 5:1 to about 1:5. In oneembodiment, the ratio of intragranular buffering agent to extragranularbuffering agent is about 1:1.

Master granules for use in the present formulations are prepared throughwet or dry granulation processes which would be apparent to one of skillin the art.

In one embodiment, a wet granulation technique is employed, wherein theat least one dissolution modifier, and the at least one buffering agentis preblended. The preblended mixture and at least one filler iscombined and wetted with purified water. This combination is then fed toan extruder where it is compressed and granules are formed. Theresultant granules are dried, using any method known in the art, such asfluid bed drying. The master granules are then screened for suitableparticle size, typically 75 um, 200 mesh. The master granules are thenblended with the nicotine active, at least one buffering agent,flavorants and sweeteners. Upon mixing and screening of this mixture, alubricant or glidant is added to the mixture. This final blend is thencompressed into a suitable lozenge.

The unit weight of lozenges of the present invention is from about 100mg to about 500 mg total weight per lozenge. In one embodiment the unitweight of the present lozenges is about one quarter that of aconventional lozenges, such as a COMMIT® lozenge (total unit weight of1.2 gms). In one embodiment the present lozenges are 200 mg to 300 mgtotal weight per lozenge.

Fillers suitable for use within the master granules of the presentinvention include, but are not limited to, maltitol, maltose, fructose,glucose, trehalose, sorbital, sucrose, sugar, mannitol, xylitol,isomalt, dextrose, maltodextrin, dextrates, dextrin, erythritol,lactitol, polydextrose and mixtures thereof. In one embodiment, thefiller is mannitol. In one embodiment, the mannitol is present fromabout 100 mg to about 300 mg per lozenge, in another embodiment fromabout 150 mg to about 200 mg per lozenge.

Dissolution modifiers suitable for use in the present invention include,but are not limited to, acacia, agar, alginic acid or a salt thereof,carbomer, carboxymethylcellulose, carrageenan, cellulose, chitosan,copovidone, cyclodextrins, ethylcellulose, gelatin, guar gum,hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropylcellulose, hypromellose, inulin, methylcellulose, pectin, polycarbophilor a salt thereof, polyethylene glycol, polyethylene oxide, polyvinylalcohol, pullulan, starch, tragacanth, trehalose, xanthan gum andmixtures thereof. In one embodiment, the dissolution modifiers includedwithin the formulations of the present invention are selected from thegroup consisting of alginic acid or a salt thereof, polycarbophil or asalt thereof, xanthan gum and mixtures thereof. In one embodiment,sodium alginate, calcium polycarbophil and xanthan gum are incorporatedwithin the master granules of the present invention. The amount ofdissolution modifier present in the master granules of the presentinvention is from about 10 mg to about 30 mg per lozenge, in anotherembodiment from about 15 mg to about 25 mg per lozenge.

Optional excipients may also be incorporated in the formulations of thepresent invention. These optional excipients may include taste maskingagents.

Taste masking agents suitable for incorporation within theextra-granular space of the present invention include intensivesweetening agents and/or flavorants. Suitable intensive sweeteningagents include, but are not limited to, aspartame, acesulfame K,cyclamate and salts thereof, glycyrrhizin and salts thereof,neohesperidine, sucralose, saccharin and salts thereof, thaumatin andmixtures thereof. Suitable flavorants include, but are not limited to,menthol, peppermint, wintergreen, sweet mint, spearmint, vanillin,chocolate, coffee, cinnamon, clove, tobacco, citrus and fruit flavorsand mixtures thereof. When present, taste masking agents are present inan amount from about 1 mg to about 50 mg per lozenge.

Additional optional excipients may also be included in the formulationsof the present invention, such as processing and stabilizing aids.Processing and stabilizing aids include, but are not limited to,chelating agents, anti-oxidants or preservatives, glidants orlubricants, or colorants. Antioxidants/preservatives suitable for use inthe present invention may include sodium benzoate, butyl-hydroxy tolueneand tocopherol and its salts. Glidants/lubricants suitable for useherein include, but are not limited to, talc, corn starch, stearic acid,calcium stearate, polyethylene glycol, colloidal silicon dioxide, sodiumstearyl fumarate, magnesium stearate, vegetable and mineral oils andmixtures thereof. In one embodiment the lubricant is magnesium stearate.Suitable colorants for use herein include any pigments, dyes, lakes ornatural food colors that are suitable for food and drug applications,eg. FD&C dyes and lakes. Where processing and stabilizing aids areincorporated within the extra-granular portion of the present invention,the total of such aids is from about 1 mg to about 25 mg per lozenge.

Lozenges of the present invention are useful as a tobacco replacement,and as a means to reduce or stop tobacco use. The compositions may beused as a total or partial replacement of tobacco, and may be usedconcurrently with tobacco as part of a planned tobacco reductionprogram, e.g., while reducing tobacco usage prior to outright quittingtobacco usage. A user may consume a lozenge of the present invention atset intervals throughout the day as part of a tobacco quit regime.Alternatively, a user may consumer a lozenge of the present inventionintermittently in response to an acute nicotine craving. In oneembodiment a user may consumer a lozenge of the present invention atboth predetermined intervals as well as intermittently throughout theday to assist with craving relief.

Lozenges of the present invention are intended to deliver the sameamount of nicotine to an individual as traditional NRT lozenge or gumproducts. However, lozenges of the present invention are smaller thantraditional lozenges, and dissolve more rapidly once administered to theoral cavity of the user. In one embodiment the in vivo dissolution timeof a lozenge of the present invention ranges from about 5 minutes toabout 25 minutes and on average the in vivo dissolution time is about 10times faster than that of a traditional lozenge. In another embodiment,the in vivo dissolution time of a lozenge of the present invention isless than about 15 minutes. This shortened retention time in the mouthresults in improved user compliance, i.e. a user is more likely to sucka lozenge to completion and therefore experience the maximum benefit.

FIG. 3 demonstrates the bioequivalence of a formulation of the presentinvention versus the formulation of a traditional lozenge. The extent(Cmax) and total exposure (AUC) of nicotine delivered by the currentinvention is the same as that delivered by a traditional lozenge.

The present invention also relates to methods of reducing tobacco usage,comprising administering a composition of the present invention to aperson in need thereof. The present invention also relates to a methodof reducing nicotine withdrawal symptoms comprising administering thecompositions of the present invention to a person in need of suchrelief. “Need” is intended to include a person's desire to reducetobacco usage or nicotine withdrawal symptoms, respectively. “Reducing”nicotine withdrawal symptoms or tobacco usage includes eliminatingnicotine withdrawal symptoms or tobacco usage.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following examples, therefore, are to beconstrued as merely illustrative and not a limitation of the scope ofthe present invention.

Examples 1, 3 and 4 exemplify the formulations of the current invention.Examples 2 and 5 are supplied for comparative purposes. Example 2 is atraditional lozenge composition wherein all buffering agents are presentin the master granules. Example 5 is a lozenge composition wherein allbuffering agents are present in the master granules, but wherein thetotal amounts of potassium bicarbonate and sodium carbonate arecomparable to those present in Examples 1, 3 and 4 of the presentinvention.

Examples 1-5 are prepared in the following manner: (1) master granulesare first prepared by wet granulation of the ingredients listed and arethen subsequently dried, (2) the master granules are then mixed with theremaining ingredients, and (3) the combined mixture is compressed into250 mg total weight lozenges

TABLE 1 Formulations of the Present Invention and Comparative ExamplesExample 1 Example 2 Example 3 Example 4 Example 5 Master granules 187.331158.57 198.44 201.22 424.22 Mannitol 165.79 1025.34 175.62 178.08375.43 Potassium 0.45 2.80 0.48 0.48 1.02 bicarbonate Sodium carbonate3.67 22.75 3.89 3.94 8.31 Sodium alginate 10.30 63.70 10.91 11.07 23.33Calcium 5.13 31.73 5.44 5.51 11.62 polycarbophil Xanthan gum 1.99 12.252.10 2.13 4.5 Nicotine polacrilex 22.22 22.22 11.11 8.33 22.22 Sodiumcarbonate 4.63 4.63 4.63 Potassium bicarbonate 0.58 0.58 0.58 Aspartame6.00 Acesulfame K 1.50 1.50 1.50 1.50 Flavorant 31.25 1.20 31.25 31.2531.25 Magnesium stearate 2.50 12.00 2.50 2.50 2.50 Total Weight in mg250 1200 250 250 482

The bioequivalence analysis of a formulation of Example 1 of the presentinvention versus the traditional comparative lozenge of Example 2 isprovided in the following table:

TABLE 2 Bioequivalent Analysis of Example 1 and Example 2 % Confidencemean Interval Example 1 Example 2 ratio (90%) Cmax 7.23 7.58 95.487.4-104.0 AUC (0-t) 24.40 25.64 95.2 89.5-101.2 AUC (o-inf) 28.69 30.2194.9 89.0-101.2

Lozenges of the formulations of Examples 1 and 2 were given to 28subjects. The in vivo dissolution time (the time in which it tookpatients to consume or dissolve lozenges in their mouths) was recordedafter patients reported and examined by clinical personnel to confirm noresidues or particles in their oral cavities. The data presented in thefollowing table indicates the faster dissolution that is achieved withthe smaller formulations of the present invention.

TABLE 3 Dissolution Time of Lozenges of Example 1 vs. Example 2 In VivoDissolution Time (in Minutes) Subject No. Example 1 Example 2 Difference 1 8.8  2 10.4 20.8 10.4  3 14.1 18.6 4.5  4 13.9 18.9 5  5 12.7 16 3.3 6 14  7 5.6 13.8 8.2  8 8.3  9 11 22.8 11.8 10 7 16.6 9.6 11 13.1 30.617.5 12 11.2 16.9 5.7 13 7.7 16.8 9.1 14 8.2 16 7.8 15 10.8 19.8 9 1613.1 23.2 10.1 17 8.2 18.6 10.4 18 7.7 19 17.4 18.4 1 20 17.3 22 4.7 2125.7 38.8 13.1 22 12.9 22.9 10 23 19.3 45.6 26.3 24 12.1 13.8 1.7 25 1326.5 13.5 26 9.6 16.5 6.9 27 15.7 30.7 15 28 20.2 26.1 5.9 Mean 12.5921.25 9.19

1. An oral lozenge composition comprising: a) a master granule componentcomprising: at least one an alkaline buffering agent; at least onedissolution modifier; and at least one filler; b) a nicotine active; andc) at least one alkaline buffering agent.
 2. The oral lozengecomposition of claim 1 wherein the master granules are obtained throughwet or dry granulation.
 3. The oral lozenge composition of claim 1wherein the at least one dissolution modifier is selected from the groupconsisting of acacia, agar, alginic acid or a salt thereof, carbomer,carboxymethylcellulose, carrageenan, cellulose, chitosan, copovidone,cyclodextrins, ethylcellulose, gelatin, guar gum, hydroxyethylcellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose,hypromellose, inulin, methylcellulose, pectin, polycarbophil or a saltthereof, polyethylene glycol, polyethylene oxide, polyvinyl alcohol,pullulan, starch, tragacanth, trehalose, xanthan gum and mixturesthereof.
 4. The oral lozenge composition of claim 3 wherein the at leastone dissolution modifier is selected from the group consisting ofalginic acid or a salt thereof, polycarbophil or a salt thereof, xanthangum and mixtures thereof.
 5. The oral lozenge composition of claim 4wherein the at least one dissolution modifier is selected from the groupconsisting of sodium alginate, calcium polycarbophil, xanthan gum andmixtures thereof.
 6. The oral lozenge composition of claim 5 wherein theat least one dissolution modifier is xanthan gum.
 7. The oral lozenge ofclaim 1 wherein the nicotine active is nicotine polacrilex.
 8. The orallozenge of claim 1 wherein the filler is mannitol.
 9. The oral lozengeof claim 1 wherein the alkaline buffering agents are selected from thegroup consisting of sodium carbonate, sodium bicarbonate, potassiumphosphate, potassium carbonate and potassium bicarbonate, and mixturesthereof.
 10. The oral lozenge of claim 1 further comprising at least oneoptional excipient selected from the group consisting of taste maskingagents, sweetening agents, flavorants, chelating agents, antioxidants,glidants or colorants.
 11. The oral lozenge of claim 1 wherein the unitweight of the oral lozenge is from about 100 mg to about 500 mg.
 12. Theoral lozenge of claim 11 wherein the oral lozenge dissolves in less than15 minutes upon administration to the oral cavity.
 13. A nicotinecontaining lozenge composition with improved user compliance prepared bythe process of: a) granulating at least one alkaline buffering agent, atleast one dissolution modifier and at least one filler into a mastergranulation, b) mixing said master granulation with a nicotine activeand an alkaline buffering agent; and c) directly compressing saidmixture into oral lozenge dosage forms.
 14. The nicotine containinglozenge composition with improved user compliance prepared by theprocess of claim 13 wherein the unit weight of the oral lozenge dosageform is from about 100 mg to about 500 mg.
 15. The nicotine containinglozenge composition with improved user compliance prepared by theprocess of claim 14 wherein the unit weight of the oral lozenge dosageform is about 250 mg.
 16. The nicotine containing lozenge compositionwith improved user compliance prepared by the process of claim 14wherein the oral lozenge dosage form dissolves in less than 15 minutesupon administration to the oral cavity.
 17. The nicotine containinglozenge composition with improved user compliance prepared by theprocess of claim 12 further comprising at least one optional excipientselected from the group consisting of taste masking agents, sweeteningagents, flavorants, chelating agents, antioxidants, glidants orcolorants.
 18. A nicotine containing lozenge composition which providesincreased maximum pH in the oral cavity and fast nicotine absorptionprepared by the process of: a) granulating at least one alkalinebuffering agent, at least one dissolution modifier and at least onefiller into a master granulation, b) mixing said master granulation witha nicotine active and an alkaline buffering agent; and c) directlycompressing said mixture into an oral lozenge formulation.